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Structural Organization of the Retriever-CCC endosomal recycling complex

ABSTRACT: Plasma membrane proteomics, with label-free quantitation comparing all mutant groups to WT. LUM2_1073550: EV_rep1 LUM2_1073551: WT_rep1 LUM2_1073552: W6D_rep1 LUM2_1073553: S829E_rep1 LUM2_1073554: G902E_rep1 LUM2_1073555: G325E_rep1 LUM2_1076766: EV_rep2 LUM2_1076767: WT_rep2 LUM2_1076768: W6D_rep2 LUM2_1076769: S829E_rep2 LUM2_1076770: G902E_rep2 LUM2_1076771: G325E_rep2 LUM2_1077992: EV_rep3 LUM2_1077993: WT_rep3 LUM2_1077994: W6D_rep3 LUM2_1077995: S829E_rep3 LUM2_1077996: G902E_rep3 LUM2_1077997: G325E_rep3

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Ezra Burstein

PROVIDER: MSV000092104 | MassIVE | Mon Jun 05 10:20:00 BST 2023

REPOSITORIES: MassIVE

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Structural organization of the retriever-CCC endosomal recycling complex.

Project description:The recycling of membrane proteins from endosomes to the cell surface is vital for cell signaling and survival. Retriever, a trimeric complex of vacuolar protein-sorting-associated protein (VPS)35L, VPS26C and VPS29, together with the CCC complex comprising coiled-coil domain-containing (CCDC)22, CCDC93 and copper metabolism domain-containing (COMMD) proteins, plays a crucial role in this process. The precise mechanisms underlying retriever assembly and its interaction with CCC have remained elusive. Here, we present a high-resolution structure of retriever in humans determined using cryogenic electron microscopy. The structure reveals a unique assembly mechanism, distinguishing it from its remotely related paralog retromer. By combining AlphaFold predictions and biochemical, cellular and proteomic analyses, we further elucidate the structural organization of the entire retriever-CCC complex across evolution and uncover how cancer-associated mutations in humans disrupt complex formation and impair membrane protein homeostasis. These findings provide a fundamental framework for understanding the biological and pathological implications associated with retriever-CCC-mediated endosomal recycling.

| S-EPMC11260360 | biostudies-literature

Structural Organization of the Retriever-CCC Endosomal Recycling Complex.

Project description:The recycling of membrane proteins from endosomes to the cell surface is vital for cell signaling and survival. Retriever, a trimeric complex of VPS35L, VPS26C and VPS29, together with the CCC complex comprising CCDC22, CCDC93, and COMMD proteins, plays a crucial role in this process. The precise mechanisms underlying Retriever assembly and its interaction with CCC have remained elusive. Here, we present the first high-resolution structure of Retriever determined using cryogenic electron microscopy. The structure reveals a unique assembly mechanism, distinguishing it from its remotely related paralog, Retromer. By combining AlphaFold predictions and biochemical, cellular, and proteomic analyses, we further elucidate the structural organization of the entire Retriever-CCC complex and uncover how cancer-associated mutations disrupt complex formation and impair membrane protein homeostasis. These findings provide a fundamental framework for understanding the biological and pathological implications associated with Retriever-CCC-mediated endosomal recycling.

| S-EPMC10274727 | biostudies-literature

Structural Organization of the Retriever-CCC Endosomal Recycling Complex.

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Structural Organization of the Retriever-CCC endosomal recycling complex

Project description:PM proteomics by TMT6plex, comparing WT to EV. 126: EV, rep1 127: EV, rep2 128: EV, rep3 129: WT, rep1 130: WT, rep2 131: WT, rep3

2023-06-05 | MSV000092103 | MassIVE

Structural Organization of the Retriever-CCC endosomal recycling complex

Project description:Protein-protein interaction analysis in Huh7 cells expressing specific VPS35L mutations. LUM2_1066594: EV_rep1 LUM2_1066595: WT_rep1 LUM2_1066596: W6D_rep1 LUM2_1066597: S829E_rep1 LUM2_1066598: G902E_rep1 LUM2_1066599: G325E_rep1 LUM2_1068615: EV_rep2 LUM2_1068616: WT_rep2 LUM2_1068617: W6D_rep2 LUM2_1068618: S829E_rep2 LUM2_1068619: G902E_rep2 LUM2_1068620: G325E_rep2 LUM2_1070655: EV_rep3 LUM2_1070656: WT_rep3 LUM2_1070657: W6D_rep3 LUM2_1070658: S829E_rep3 LUM2_1070659: G902E_rep3 LUM2_1070660: G325E_rep3

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Structural Organization of the Retriever-CCC endosomal recycling complex

Project description:Protein-protein interaction proteomics from blue native gels with iBAQ quantification. Samples were run on native gels and corresponding molecular weight ranges were cut out. LUM2_1049862: HeLa, 720kDa LUM2_1049863: HeLa, 480kDa LUM2_1049864: HeLa, 240kDa LUM2_1049865: Commd1 IP, 720kDa LUM2_1049866: Commd1 IP, 480kDa LUM2_1049867: Commd1 IP, 240kDa LUM2_1049868: VPS26C, 720kDa LUM2_1049869: VPS26C, 480kDa LUM2_1049870: VPS26C, 240kDa

2023-06-05 | MSV000092100 | MassIVE

Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling.

Project description:Following endocytosis into the endosomal network, integral membrane proteins undergo sorting for lysosomal degradation or are retrieved and recycled back to the cell surface. Here we describe the discovery of an ancient and conserved multiprotein complex that orchestrates cargo retrieval and recycling and, importantly, is biochemically and functionally distinct from the established retromer pathway. We have called this complex 'retriever'; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. We establish that retriever associates with the cargo adaptor sorting nexin 17 (SNX17) and couples to CCC (CCDC93, CCDC22, COMMD) and WASH complexes to prevent lysosomal degradation and promote cell surface recycling of α5β1 integrin. Through quantitative proteomic analysis, we identify over 120 cell surface proteins, including numerous integrins, signalling receptors and solute transporters, that require SNX17-retriever to maintain their surface levels. Our identification of retriever establishes a major endosomal retrieval and recycling pathway.

| S-EPMC5790113 | biostudies-literature

Endosomal PI(3)P regulation by the COMMD/CCDC22/CCDC93 (CCC) complex controls membrane protein recycling.

Project description:Protein recycling through the endolysosomal system relies on molecular assemblies that interact with cargo proteins, membranes, and effector molecules. Among them, the COMMD/CCDC22/CCDC93 (CCC) complex plays a critical role in recycling events. While CCC is closely associated with retriever, a cargo recognition complex, its mechanism of action remains unexplained. Herein we show that CCC and retriever are closely linked through sharing a common subunit (VPS35L), yet the integrity of CCC, but not retriever, is required to maintain normal endosomal levels of phosphatidylinositol-3-phosphate (PI(3)P). CCC complex depletion leads to elevated PI(3)P levels, enhanced recruitment and activation of WASH (an actin nucleation promoting factor), excess endosomal F-actin and trapping of internalized receptors. Mechanistically, we find that CCC regulates the phosphorylation and endosomal recruitment of the PI(3)P phosphatase MTMR2. Taken together, we show that the regulation of PI(3)P levels by the CCC complex is critical to protein recycling in the endosomal compartment.

| S-EPMC6753146 | biostudies-literature

Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling

Project description:Following endocytosis into the endosomal network, integral membrane proteins undergo sorting for lysosomal degradation or are retrieved and recycled back to the cell surface. Here we describe the discovery of an ancient and conserved multiprotein complex which orchestrates cargo retrieval and recycling and importantly, is biochemically and functionally distinct to the established retromer pathway. Composed of a heterotrimer of DSCR3, C16orf62 and VPS29, and bearing striking similarity with retromer, we have called this complex ‘retriever’. We establish that retriever associates with the cargo adaptor sorting nexin 17 (SNX17) and couples to CCC (CCDC93, CCDC22, COMMD) and WASH complexes to prevent lysosomal degradation and promote cell surface recycling of α5β1-integrin. Through quantitative proteomic analysis we identify over 120 cell surface proteins, including numerous integrins, signalling receptors and solute transporters, which require SNX17-retriever to maintain their surface levels. Our identification of retriever establishes a major endosomal retrieval and recycling pathway.

2018-01-15 | PXD007230 | Pride

Structural basis for Retriever-SNX17 assembly and endosomal sorting.

Project description:During endosomal recycling, Sorting Nexin 17 (SNX17) facilitates the transport of numerous membrane cargo proteins by tethering them to the Retriever complex. Despite its importance, the mechanisms underlying this interaction have remained elusive. Here, we report the structure of the Retriever-SNX17 complex determined using cryogenic electron microscopy (cryo-EM). Our structure reveals that the C-terminal tail of SNX17 engages with a highly conserved interface between the VPS35L and VPS26C subunits of Retriever. Through comprehensive biochemical, cellular, and proteomic analyses, we demonstrate that disrupting this interface impairs the Retriever-SNX17 interaction, subsequently affecting the recycling of SNX17-dependent cargos and altering the composition of the plasma membrane proteome. Intriguingly, we find that the SNX17-binding pocket on Retriever can be utilized by other ligands that share a consensus acidic C-terminal tail motif. By showing how SNX17 is linked to Retriever, our findings uncover a fundamental mechanism underlying endosomal trafficking of critical cargo proteins and reveal a mechanism by which Retriever can engage with other regulatory factors.

| S-EPMC10980035 | biostudies-literature

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